Despite convincing evidence for a host's ability to mount immune responses to a large number of cancer-associated gene products, most patients with advanced malignancies still succumb to their disease. One means by which a host may fail to adequately mount an effective anti-tumor immune response is ineffective priming of the immune system in tumor antigen presentation. We have investigated a strategy to augment antigen presentation involving vaccination with autologous, irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF). A majority of metastatic lesions resected after vaccination of patients with metastatic melanoma and non-small cell lung cancer showed brisk or focal T lymphocyte and plasma cell infiltrates with tumor necrosis. While significant numbers of patients achieved durable clinical responses to this vaccination strategy, most eventually develop progressive disease. One mechanism that may limit the therapeutic potency of cancer vaccines is the attenuation of T cell function by CTLA-4. In murine models, concurrent administration of CTLA4 antibody blockade with vaccination with irradiated, GM-CSF secreting tumor cells increases the rejection of poorly immunogenic tumors. To gain a preliminary assessment of the biologic activity of CTLA4 blockade in humans, we treated previously vaccinated patients with metastatic melanoma and ovarian carcinoma with the humanized monoclonal antibody MDX-CTLA4. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous GM-CSF secreting tumor cells. Potential synergies of MDX-CTLA4 and GM-CSF-based vaccines need further exploration. Currently, we are performing phase I trials of GM-CSF based vaccines using lethally irradiated, autologous tumor cells in patients with metastatic melanoma, metastatic non-small call lung cancer, advanced ovarian cancer, and acute myelogenous leukemia (AML)/advanced myelodysplasia. This offers the unique opportunity to further evaluate the safety and efficacy of this combination therapy in a variety of malignancies, as well as explore antigen-specific changes in T cell responses as a function on CTLA-4 blockade.